The long term goal is to understand the molecular basis of mouse CD1d1 restricted NKR- P1+ natural T (NTab) cell's immune function in health and in human disease. The objectives of this application are to investigate the role of the major ligand, glycophoshatidylinositol (GPI), associated with CD1d1 in controlling NTab cell function, the structural features of recognition of the glycolipid ligand when presented by CD1d1, the in vivo assembly site of CD1d1, as well as to determine whether glycolipid binding is a common feature of CD1 molecules. The rationale behind the research is that the molecular basis of CD1d1 and NTab cell interaction is yet undefined. CD1d1 controls NTab cell development and function. Because CD1d1 is naturally occupied predominantly (>95%) with the cellular glycolipid GPI, the development and function of NTab cells must be dependent on this ligand presented by CD1d1. Thus the central hypothesis to be tested is that mouse CD1d1 controls the immune function of NTab cells by the presentation of its major natural ligand, GPI. To achieve the objective of this proposal they will pursue four specific aims: (1) determine whether mouse CD1d1 controls NTab cell's function by presenting GPI; (2) determine the fine specificity of NTab cells for the ligand presented by CD1d1; (3) determine the intracellular site of CD1d1 assembly with GPI; (4) determine whether association of with cellular glycolipid is a common feature of CD1 molecules. They expect that, at the conclusion of the proposed period of support, they will have determined precisely how CD1d1 assembles with GPI. Additionally, the chemical nature of the natural ligand(s) associated with human CD1b and human CD1d will have been characterized. Together, the results from these studies will provide clues as to whether mouse CD1d1 can present antigen to T lymphocytes and what their nature will be. A counterpart of mouse NTab.cell, the Va2JaQ/Vb11 Tcr+ CD4-8- T cells, whose function is controlled by human CD1d1, the homologue of mouse CD1d1, exists in people. Thus, our studies on the molecular basis of how CD1d1 controls cell function should facilitate an understanding of the Th1-Th2 paradigm in health and human diseases. Insights from the above studies could eventually result in new therapeutic strategies.